Gonadal steroids are major neuroregulators and presumably underlie gender-related differences (sexual dimorphisms) in brain structure and function. We have studied reproductive endocrine-related mood disorders as well as developed endocrine models for these disorders in order to characterize the role of gonadal steroids in affective disturbance. In the past year, our major findings are as follows: 1) estrogen or progesterone precipitates return of premenstrual syndrome symptoms in women successfully treated by medication (leuprolide)-induced hypogonadism but not in women lacking a history of premenstrual syndrome. Premenstrual syndrome, therefore, represents an abnormal response to normal hormone levels. 2) Progesterone, but not estradiol, increases cortisol (significantly) and ACTH (trend) secretion compared with an induced hypogonadal condition (n = 8). Similar increased cortisol levels are seen following dexamethasone during progesterone replacement. These data may help explain observed menstrual cycle phase-related differences or sexual dimorphisms in the stress response. For example, the ACTH and AVP responses to exercise stimulation in women are increased in the luteal phase. Further, preliminary data show that the ACTH response to exercise stimulation is higher in males than in females, and in contrast to women, men show no difference in stimulated pituitary-adrenal response during hypogonadal compared with eugonadal conditions. 3) Non-depressed postmenopausal women differ in their ability to discriminate estradiol (3/8) or progesterone (2/7) from placebo. These data identify, for the first time, that gonadal steroids are discriminable in some, but not all, human subjects and provide an independent potential model for examining the differential behavioral sensitivity to gonadal steroids seen in women with premenstrual syndrome. 4) Preliminary data show no differences in the frequency of candidate gene (serotonin transporter, 2A, 2C receptors) polymorphisms in women with premenstrual syndrome compared with controls. 5) Euthymic women with a history of postpartum depression appear differentially sensitive to changes in gonadal steroid levels, as they, but not controls, experience significant depression during blinded withdrawal from high dose gonadal steroid administration. These observations, then, demonstrate not only the marked impact of gonadal steroids on neuroendocrine function and behavior in humans, but demonstrate as well, in parallel with our findings in women with premenstrual syndrome, that women with histories of reproductive endocrine-related mood disorders display abnormal responses to normal levels of gonadal steroids.